In the United States, Neisseria gonorrhoeae (also know as Ng, the gonococcus) infections are the second most common notifiable infectious disease, with annual associated health costs exceeding one billion dollars. An estimated 106 million new cases occur globally each year (1), and greater than 800,000 cases occurred in the United States in 2012 (2, 3). The reported number of cases of antibiotic resistant Ng strains is increasing, further complicating the treatment efforts of this transmittable disease. Thus, the continued prevalence of Ng, and its associated morbidity support an urgent need for continued efforts to develop and implement novel Ng diagnostics, therapeutics, and vaccines.
Gonococcal vaccine development has proven to be exceptionally difficult. This is alarming in view of the increasing global prevalence of multidrug resistant (MDR) Ng, with increasing reports of treatment failures, and the recent emergence of untreatable MDR Ng strains (4-12). In 2013, the Center's for Disease Control (CDC) announced that Ng was one of three bacteria that represented an urgent threat with regard to increasing antibiotic-resistance (13). MDR Ng is of particular concern in developing countries, which are heavily impacted by gonococcal diseases and where diagnosis and treatment rely heavily upon a syndromic approach (i. e., the treatment of all at risk patients based upon the presence of symptoms rather than a definitive diagnosis) (14-16). The global medical community's management of Ng further contributes to antibiotic-resistance by the overuse and misuse of antibiotics (14-16). Thus, there is an urgent need for the identification of novel therapeutics that can be rapidly translated into clinical use and for which the gonococcus is unlikely to develop resistance.
AR-12 (previously known as OSU-03012) is a celecoxib derivative that was discovered at The Ohio State University. The compound was initially developed in the oncology setting and a phase I study demonstrated an acceptable safety profile with long-term oral exposures up to 33 weeks. The AR-12 oncology dose most likely substantially exceeds the exposure needed in the infectious disease setting. AR-12 (a.k.a. OSU-03012) has been previously shown to exhibit anti-tumor and anti-bacterial activity. It is thought that AR-12 induces autophagy of cells harboring intracellular bacteria. Supportive preclinical studies demonstrated that AR-12 has rapid blood brain barrier penetration and appreciable accumulation in tissues, exceeding the blood level concentrations several fold. (36).
AR-12 was initially developed by Arno Therapeutics (Arno) in 2008 for an oncology indication. In support of this oncology program, Arno initiated an Investigational New Drug (IND) enabling toxicology program, which included standard Good Laboratory Practice (GLP) tests (e. g. genotoxicity), a battery of safety pharmacology studies, and 28-day general toxicity assessments performed in rats and dogs. Before Arno's involvement, the National Cancer Institute had generated preclinical ADME (i. e., absorption, distribution, metabolism, and excretion) and toxicology data in the mouse model as part of the Rapid Access to Intervention Development (RAID) program. AR-12 synthesis was optimized and scaled-up to approximately 50 kg (purity >99.5%; stability ≥24 months at ambient conditions) under Current Good Manufacturing Practices (cGMP) conditions in anticipation of continued clinical development in the oncology setting.
AR-12 was originally investigated in a Phase I oncology study (27), an IND (IND #103799) was previously filed with the Food and Drug Administration (FDA), and an Investigational Medicinal Product Dossier (IMPD) was filed with the Medicines and Healthcare Products Regulatory Agency (MHRA Reference: 35725/0001/001-0001 [EudraCT Number: 2009-014285-25]) in the United Kingdom, which enabled the Phase I study entitled: “A Phase I Study of AR-12 (2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide) in Adult Patients With Advanced or Recurrent Solid Tumors or Lymphoma, for Which No Standard Therapy Is Available”. At doses appropriate in the oncology setting, the dose limiting toxicities (DLT) included: fatigue, dizziness, and skin rash. Thirty-five patients were enrolled at nine dose levels. With the original formulation tested, the recommended oncology Phase II dose was 800 mg twice daily. It is anticipated that the doses required in the infectious disease setting will be significantly below the doses required in the oncology arena, based on various preclinical studies in multiple pathogens.
Pharmacokinetic data from this Phase I study show that high blood levels of AR-12 can be obtained using on oral dosage form. The half-life in humans is long and is estimated to be approximately 60 hours. Early preclinical studies in the mouse model show that AR-12 permeates into tissues and tissue concentrations can significantly exceed blood levels. This is a favorable property for the treatment of Ng, which is, with rare exception, a mucosal pathogen. AR-12 is slowly released from the tissue back into the bloodstream and slowly excreted, which explains its long half-life.